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Molecular Mechanisms of Type 2 Diabetes Mellitus

NCT00816218 · Status: COMPLETED · Phase: PHASE4 · Type: INTERVENTIONAL · Enrollment: 39

Last updated 2012-05-31

No results posted yet for this study

Summary

This project is designed to evaluate the molecular mechanisms involved in the early development of endothelial dysfunction in type 2 diabetic patients. The investigators intend to correlate increases in insulin signaling pathway activity following pioglitazone therapy with improvements in nitric oxide synthase expression in skeletal muscle. In addition, the investigators will evaluate vascular responses and in vivo nitric oxide release during administration of acetylcholine and nitroprusside in patients with type 2 diabetes. Enhanced knowledge of the molecular mechanisms responsible for endothelial dysfunction, an early abnormality in the pathogenesis of atherosclerosis, is critical before novel therapies to arrest or delay the appearance of cardiovascular complications in diabetes can be developed.

The investigators intend to recruit fifty type 2 diabetic patients treated with diet alone or diet plus sulfonylureas or meglitinides and add Pioglitazone (45 mg), an insulin sensitizer, for 6 months. In addition to assessment of clinical and metabolic parameters, insulin sensitivity and brachial artery and skin microcirculatory responses to acetylcholine and nitroprusside in combination with simultaneous determination of nitric oxide release will be documented before, 3 and 6 months after Pioglitazone therapy is initiated. Circulating levels of markers of endothelial damage (VCAM, ICAM, selectins), inflammation (C-reactive protein and interleukins), increased coagulability (PAI-1) as well as lipids and apolipoproteins will measured during the study. Skeletal muscle biopsies will be performed during the euglycemic insulin clamp before and 6 months after therapy for measurements of NO synthase activity and key elements of the insulin signal transduction pathway involved in the regulation of glucose metabolism (IRS-1, PI-3 kinase, PI-3 kinase associated with IRS-1 and the mitogenesis MAP-kinase.

Type 2 diabetes confers a substantial increase in the risk of cardiovascular disease. This is believed to be due, in part, to endothelial dysfunction, which correlates closely with impaired vascular responsiveness. Our study will clarify further the extent to which resistance to insulin action and impaired nitric oxide release from endothelial cells are interrelated. We also expect to demonstrate that insulin sensitizers (pioglitazone) can help to restore normal endothelial function, and ultimately prevent/delay the appearance of vascular disease in patients with type 2 diabetes.

Conditions

Interventions

DRUG

Pioglitazone

pioglitazone, 45 mg daily

Sponsors & Collaborators

  • Takeda

    collaborator INDUSTRY

  • The University of Texas Health Science Center at San Antonio

    lead OTHER

Principal Investigators

  • Eugene Cersosimo, MD · The University of Texas Health Science Center at San Antonio

Study Design

Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Model
PARALLEL

Eligibility

Min Age
18 Years
Max Age
65 Years
Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2003-03-31
Primary Completion
2006-07-31
Completion
2008-11-30

Countries

  • United States

Study Locations

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Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT00816218 on ClinicalTrials.gov